Foot-and-Mouth Disease (FMD) is the most contagious animal disease. The causative agent, Foot-and-Mouth Disease Virus (FMDV), is an aphthovirus of the Picornaviridae family that has a positive sense RNA genome encoding four capsid proteins (VP1-VP4) and non-structural polypeptides (2A-2C and 3A-3D) (review by Carrillo, C. et al, 2005).
FMDV rapidly replicates and can spread through the air (aerosol transmittable) among infected and in-contact susceptible animals, including cloven-hoofed animals such as cattle, pigs, sheep and goats. FMD is on the A list of animal infectious disease of the Office International des Epizooties (OIE) and has been recognized as the most important constraint to international trade in animals and animal products. Currently, FMD is controlled by quarantine and destruction of infected and exposed animals; and, in most countries, by vaccination with chemically inactivated virus compositions. Because of the detrimental economic consequences resulting from its presence, countries that are free of the disease have introduced a number of measures to retain this status without vaccination.
Seven distinct serotypes of FMDV have been described and each serotype is further divided into multiple subtypes. These serotypes include: A, O, C, Asia, and the South African types SAT-1, 2, and 3, with A, O, and Asia being the most common. Adding to the genetic complexity and variability of the virus, FMDV can mutate at a high rate on a random basis.
A significant difficulty in formulating vaccines for FMDV is the remarkable antigenic diversity of the virus and the lack of cross-protection between serotypes. That is, animals vaccinated against, or recovered from, a virus of one serotype are susceptible to infection with viruses from the remaining six serotypes. Moreover, the degree of antigenic variation within a serotype is such that a vaccine effective against one subtype may not be protective against another subtype within that same serotype.
Current FMD vaccines contain a mixture of inactivated viruses including a reference strain of each relevant serotype or subtype, which is determined by monitoring the virus strains present in local circulation. To prevent outbreaks from emerging FMD variants, field isolates must be periodically monitored and compared to the current vaccine in production. Thus, to ensure that the vaccine is current and effective, the production of inactivated FMD virus vaccines require: (1) growing and inactivating several virus strains to be included in the vaccine, (2) monitoring the potency and efficacy of each inactivated strain, and (3) reformulating the vaccine product periodically to include current strains to prevent loss of protective efficacy by emerging new variants.
Producing and maintaining an efficient inactivated virus vaccine is onerous and complicated in view of the significant antigenic variation between and among the FMDV serotypes. Several known issues and disadvantages associated with inactivated FMDV vaccines include: biohazard and biosecurity risks, product instability and variability, and unintended, detrimental side effects in treated animals.
For example, manufacturing inactivated virus vaccines create biohazard/biosecurity risks because the virus must be produced in a high-containment facility to prevent contamination of the immediate environment. Additionally, the innocuousness of the inactivated virus product cannot be completely assured. In fact, several recent cases of FMDV in Europe have been traced to incompletely inactivated virus. These potential biohazard/biosecurity risks limit the number of qualified vaccine suppliers to just a few. Such limitations can hamper the ability of a region to effectively and immediately respond to an outbreak.
Current FMD vaccines also suffer from product instability as well as lot-to-lot variability. As discussed above, vaccines must be monitored and reformulated periodically to include both current and emerging strains of FMDV. Moreover, each region of the world will require protection from a different current/emerging strain of FMDV at any given time. Thus, complex and undefined compositions of inactivated virus vaccines being produced throughout the world. These complex mixtures of inactivated virus vaccines must be continuously inspected at regular intervals to ensure immunopotency.
In addition to the above issues, current FMDV vaccines have been shown to cause unintended, detrimental side effects in treated animals. For example, reports of allergic reactions, anaphylactic shock, and spontaneous death have been reported in animals treated with current vaccines.
The disadvantages of the existing inactivated viral lysate based commercial vaccines have encouraged research to create safer and better-defined subunit products (Brown, F. 1992). However, to be an acceptable replacement to the inactivated virus, such subunit products must have an equivalent immunogenicity to that of the inactivated virus vaccines and provide a wide spectrum of protection against antigenic variants. Most importantly, the subunit products need to meet the OIE guidelines for challenge studies after only single administration of the vaccine in order to be qualified as an FMD emergency vaccine.
To overcome some of the problems associated with existing commercial viral lysate based FMD vaccines, the inventor and her research team have made significant strides over the past 15 years in developing synthetic peptide based FMDV vaccines to protect swine from FMDV challenge. In particular, the inventor successfully developed an effective FMDV vaccine that is capable of eliciting a broad range of neutralizing antibodies against FMDV using a formulation containing an optimized VP1 looped B cell epitope peptide. Immunogenicity of this VP1 looped B cell epitope peptide can be further enhanced by covalently linking the peptide to an artificial T helper epitope (Wang, C Y and Shen, M, 2000; Wang, C Y et al, 2001; Wang, C Y, et al, 2002). This vaccine has been shown to effectively protect swine from FMDV challenge after multiple administrations of a formulation (Wang, C Y, et al. 2002). The VP1 looped B cell epitope peptide formulation has proven to be an important vaccine in protecting animals from classical FMDV virus strains.
To qualify as an “emergency” FMD vaccine under OIE protocol, a formulation must induce a rapid protective immunity with wide antigenic coverage in the FMD serotypes after only a single administration. Although multiple administrations of the VP1 looped B cell epitope peptide formulation provide effective protection against classical FMDV virus strains, single administrations of the formulation have not been able to protect swine against FMDV challenge on an emergency basis. Additionally, the VP1 looped B cell epitope peptide formulation has not been shown to protect cattle from FMDV challenge after one or two administrations (Rodriguez, LL. et al. 2003).
There is an urgent need to explore the extensive literature in the public domain, identify and validate correlates of the protective immune responses required in an FMD emergency vaccine so as to allow development of a safe and efficacious peptide based FMD vaccine and formulations thereof for emergency and general protective use against FMDV.
In view of the disadvantages and limitations of vaccines currently available for FMD, there remains an urgent need for an emergency vaccine formulation that is capable of protecting swine and cattle from FMDV after only a single administration.